It has been known in the fields of pharmaceutical products, agrochemicals, food products, and the like, that, by surface-modifying fine particles comprising an active ingredient with a water-soluble substance, or by chemically modifying an active ingredient with a water-soluble substance, the active ingredient can be suppressed from approaching to or being recognized by a protein, etc. in a living body, and thus an effect of prolonging half-life in blood, reducing antigenicity, etc. can be obtained. Further, it is known that, also in the case of fine particles comprising a lipid, a fatty acid, or a derivative thereof, such as liposome and emulsion particles, the effect of prolonging half-life in blood, reducing antigenicity, etc. can be obtained by surface-modifying the fine particles with a water-soluble substance (see Patent Documents 1 and 2).
The surface modification of the fine particles comprising the lipid, fatty acid, or derivative thereof with the water-soluble substance is carried out generally such that, in the method of producing the fine particles, at least a constituent component capable of forming particles among the constituent component is placed under the presence of a surface modifier which is a derivative of the water-soluble substance, so that the constituent component capable of forming particles and the surface modifier form the fine particles in combination (see Patent Document 2). However, when the fine particles are modified with a large amount of the surface modifier in the above process, the physicochemical properties of the fine particles may change, whereby the desired surface-modification of the fine particles may not be achieved in some cases. For example, it is known that, when a phospholipid is used under the presence of a large amount of a polyethylene glycol derivative for preparing liposome, the phospholipid forms not a lipid membrane but a micelle (see Biophysical Journal, 1997, vol. 73, p. 258-266, and Biophysical Journal, 2002, vol. 83, p. 2419-2439). Further, in the surface modification of the fine particles with the water-soluble substance, though it is only necessary to modify the outer surface of the fine particles from the viewpoint of the above mentioned purpose, the surface modifier is undesirably contained inside the fine particles in the method of using the particle component under the presence of the surface modifier for forming the fine particles.
Methods of modifying only the outer surface of the fine particles with the water-soluble substance are known (see Patent Documents 1 and 3), such as the method which forms the fine particles by using at least the constituent component capable of forming the particles among the constituent components of the fine particles comprising the lipid, fatty acid, or derivative thereof, and then the surface modifier which is a lipid derivative, fatty acid derivative, or aliphatic hydrocarbon derivative of the water-soluble substance is added to the fine particles. In the method of Patent Document 1, a polyethylene glycol-bonded phospholipid is added to liposome in water at room temperature, to surface-modify the liposome with the polyethylene glycol. To sufficiently achieve surface modification at a temperature of room temperature or lower in this method, it is only limited to the case when a phospholipid having a low phase transition temperature is used as the constituent component capable of forming the particles in the liposome in combination with a surface modifier having a high critical micelle concentration, as described also in Patent Document 3. Further, in the method described in Patent Document 3, a surface modifier which is a compound, which has a hydrophobic moiety at one end and has a hydrophilic moiety at the other end, is added to liposome in water, and the mixture is heated at the phase transition temperature of the constituent component capable of forming particles or higher, to surface-modify the liposome.
Patent Document 1: Japanese Published Unexamined Patent Application No. 149512/90
Patent Document 2: Japanese Translation of PCT International Application No. 501264/93
Patent Document 3: Japanese Published Unexamined Patent Application No. 181415/91